Jump to comment:

• Compound and double mutations in patients with hypertrophic cardiomyopathy
  Ajay Bahl
  Published on: 27 April 2016

• Published on: 27 April 2016

  Compound and double mutations in patients with hypertrophic cardiomyopathy

  • Ajay Bahl, Assistant Professor Cardiology

  Dear Editor,

  This paper by Ingles et al. has once again highlighted the role of compound and double mutations in patients with hypertrophic cardiomyopathy (HCM).[1] They detected compound or double mutations in 4 of 23 (17%) of probands found to have mutations in the genes that were screened. This large percentage of compound mutations has serious implications for any HCM mutation screening programme. Mutations in...

  Show More

  Dear Editor,

  This paper by Ingles et al. has once again highlighted the role of compound and double mutations in patients with hypertrophic cardiomyopathy (HCM).[1] They detected compound or double mutations in 4 of 23 (17%) of probands found to have mutations in the genes that were screened. This large percentage of compound mutations has serious implications for any HCM mutation screening programme. Mutations in HCM are spread across several genes and because of the logistics and cost involved, mutation screening is limited to a few labs and is time consuming. This reduces the clinical availability of the screening process. Such a high incidence of compound and double mutations would further add to the complexity and costs of the screening process.

  This data on compound and double mutations should however be interpreted with caution. Firstly, all four families were small, only one genotype positive individual in three families and three in the fourth, thus proving co-segregation of sequence variation with disease phenotype is not possible. Secondly, in none of the four families were the two mutations shown to independently give rise to the HCM phenotype. Thirdly, three of the eight compound mutations were novel and no functional studies were carried out. Fourthly, in all four families MyBP-C was involved.

  The three criteria chosen by the authors to consider a sequence variation to be disease causing are inadequate. The first criteria of co- segregation of the sequence variation with affected members obviously does not apply to such small families. The second criteria of absence of mutation in 300 unrelated chromosomes from healthy adult controls also has a rider. Some of the sequence variations are only found in specific ethnic groups for example a deletion in intron 32 of MyBP-C. On testing healthy controls, this deletion was not found in 270 Caucasians but was present in 7% of healthy controls from South India.[2] We have also found this deletion in 4.2% of healthy North Indian controls. Thus some sequence variations are restricted to and even common in particular ethnic groups. Therefore screening 150 healthy controls as the authors have done is not adequate. The ethnicity of each individual proband found to have a novel sequence variation should be determined and healthy controls from that particular ethnicity studied. In case a patient has ancestors from multiple ethnicities, healthy controls should be studied in all groups to render the data scientifically valid. The third criteria mentioned is conservation of mutated residue among species and isoforms. The degree of conservation has not been discussed at all in the manuscript. Thus it is not possible to conclude that the novel sequence variations found by the authors are disease causing. These could be at best labelled as probable mutations. They could also be disease modifying variations or just simple polymorhisms. Similar issues also arise in earlier reports of compound mutations.[3][4]

  Vast amount of data on genotyping of HCM patients is now available and a number of sequence variations have been identified. The significance of these is often not clear. As in other fields of cardiology, there is an urgent need to sort out these sequence variations. A group or a consensus committee needs to be formed that can go through all the sequence variations reported and classify them as either definite mutations, probable mutations, disease modifying variations or just polymorhisms. This then has to be continued as an ongoing process to include the data generated in the future.

  References

  1. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counseling. J Med Genet 2005;42:e59.

  2. Waldmuller S, Sakthivel S, Saadi AV et al. Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2003;35:623-36.

  3. Richard P, Charron P, Carrier L et al. Hypertrophic cardiomyopathy distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227-32.

  4. Van Driest SL, Vasile VC, Ommen SR et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903-10.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top